2026-06-14T03:33:16Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/268432025-12-18T13:01:55Zcom_20.500.12105_19586com_20.500.12105_2202col_20.500.12105_19587

00925njm 22002777a 4500 dc Asensio-Lopez, Maria Del Carmen author Ruiz-Ballester, Miriam author Pascual-Oliver, Silvia author Bastida-Nicolas, Francisco Jose author Sassi, Yassine author Fuster, Jose Javier author Pascual-Figal, Domingo author Soler, Fernando author Lax, Antonio author 2025-05-15 The causal relationship between the activation of nuclear factor erythroid 2-related factor 2 (NRF2) and the preservation of SERCA2a function in mitigating myocardial ischemia-reperfusion (mI/R) injury, along with the associated regulatory mechanisms, remains incompletely understood. This study aims to unravel how NRF2 directly or indirectly influences SERCA2a function and its regulators, phospholamban (PLN) and Dwarf Open Reading Frame (DWORF), by testing the pharmacological repositioning of AEOL-10150 (AEOL) in the context of mI/R injury. C57BL6/J, Nrf2 knockout (Nrf2), and wild-type (Nrf2) mice, as well as human induced pluripotent stem cell-derived cardiomyocytes (hiPSCMs) were subjected to I/R injury. Gain/loss of function techniques, RT-qPCR, western blotting, LC/MS/MS, and fluorescence spectroscopy were utilized. Cardiac dimensions and function were assessed by echocardiography. In the early stages of mI/R injury, AEOL administration reduced mitochondrial ROS production, decreased myocardial infarct size, and improved cardiac function. These effects were due to NRF2 activation, leading to the overexpression of the micro-peptide DWORF, consequently enhancing SERCA2a activity. The cardioprotective effect induced by AEOL was diminished in Nrf2 mice and in Nrf2/Dworf knockdown models in hiPSCMs subjected to simulated I/R injury. Our data show that AEOL-induced NRF2-mediated upregulation of DWORF disrupts the phospholamban-SERCA2a interaction, leading to enhanced SERCA2a activation and improved cardiac function. Taken together, our study reveals that AEOL-induced NRF2-mediated overexpression of DWORF enhances myocardial function through the activation of the SERCA2a offering promising therapeutic avenues for mI/R injury. Mol Med. 2025 May 15;31(1):189. Molecular Medicine 40375185 https://hdl.handle.net/20.500.12105/26843 AEOL-10150 Acute myocardial infarction Cardiac protection DWORF NRF2 Reperfusion injury AEOL-induced NRF2 activation and DWORF overexpression mitigate myocardial I/R injury.